The market for wound care, the major proportion of which is for sealants and hemostats, has grown rapidly alongside great advances in the research and development of tissue adhesives. Triggered by the FDA granting permission to a fibrin sealant in 1998, a burst of novel tissue adhesives has been appearing in the market each year. Attention is now being focused on these tissue adhesives as alternatives to those used in conventional surgical or internal operations, such as suturing, clipping, cautery, etc.
Conventional surgical techniques, such as suturing, guarantee strong tensile strength, but have the disadvantages of pain and the need for the threads to be postoperatively removed. On the other hand, tissue adhesives enjoy the advantages of a short adhesion time, simple usage, no requirements for postoperative removal, etc., but are problematic in that they exhibit low adhesiveness, poor biocompatibility and tensile strength and a remarkably decreased adhesiveness particularly in the presence of moisture. Studies have focused on conquering the problems.
The necessity for direct contact with the tissue forces tissue adhesives to have biocompatibility. Further, because they are typically used inside the body, for example, in places where they may be brought into direct contact with body fluids or blood, more stringent conditions regarding toxicity and harmfulness must be applied to medical adhesives, as well as strict standards for biocompatibility and biodegradation.
Although they must show properties corresponding to the different regions or fields to which they are applied, such as skins, vessels, digestive organs, cranial nerves, plastic surgery, orthopedic surgery, general surgery etc., tissue adhesives are required to have in common the following properties: 1) must adhere fast to target regions at room temperature under atmospheric pressure even in the presence of moisture; 2) must be free of toxicity and be capable of being sterilized; 3) must maintain sufficient mechanical strength and be in close contact with a wound surface; 4) must be biodegradable and capable of controlling hemostasis; and 5) must be effective for wound healing.
Among currently commercialized and/or utilized tissue adhesives are instant cyanoacrylate glues, fibrin glues, gelatin glues, and polyurethane. Attention has recently been paid to instant cyanoacrylate glues because of their high adhesiveness and performance. Particularly, instant glues for tissue closure, having biocompatibility, flexibility and low toxicity, have been under extensive study in advanced countries thanks to their beneficial effects including hemostasis, antibacterial activity and being able to substitute for sutures.
Cyanoacrylate tissue adhesives are commercially available under the trade names of Dermabond (Johnson & Johnson) or Indermil (US Surgical). These cyanoacrylate adhesives, consisting of a solitary material, can solidify in a short period of time at room temperature just by using water without the aid of initiators and exhibit a transparent appearance and strong adhesive strength, but low resistance to both impact and heat. Moreover, their use is now restricted due to the high toxicity and fragility thereof although cyanoacrylate adhesives are partially used in the clinical field. Fibrin glues received FDA approval first in 1998 and since then they have been applied to cardiac surgery. Active research into fibrin sealants has lead to the commercialization of products, e.g., Tisseel VH® (Baxer) and Evicel™ (Johnson & Johnson).
Together with cyanoacrylate sealants, fibrin sealants occupy a predominant share of the tissue adhesive market. Taking advantage of the clotting of fibrin, the two major ingredients of fibrin sealants are fibrinogen and thrombin in combination with calcium chloride and factor XIII. As alternatives or reinforcements to suturing, they are applied to the closure of peripheral nerves and very small blood vessels.
Fibrin sealants have several advantages over older methods of hemostasis; they speed up the formation of a stable clot independently of water in target sites, and additionally, they can form a clot in conjunction with platelets without restrictions and are excellent in biocompatibility. However, they suffer from the disadvantages of weak adhesive strength, fast biodegradation and infection risk.
Gelatin glues, derived from the body, are a kind of tissue adhesive developed with gelatin-resorcinol-formalin (GRF). In addition, there are tissue adhesives made of gelatin-glutaraldehyde. Although these tissue adhesives provide high adhesiveness, formalin or glutaraldehyde undergo crosslinking reactions with proteins of the target tissues, giving rise to tissue toxicity.
Developed as flexible adhesives, polyurethane adhesives can maintain the closures in their natural state following solidification. These adhesives absorb water from tissue surfaces to stick themselves fast to the tissues. They react with water to be cured within several minutes and the cured adhesives biodegrade properly in addition to being flexible. However, aromatic diisocyanate, a material used in polyurethane adhesives, is toxic to the body.
Thus, the tissue adhesives developed so far still have disadvantages in terms of toxicity and weak adhesiveness. As a solution to these problems, 3,4-dihydroxyphenyl-L-alanine (DOPA) is becoming popular and is under intensive study.
Dopa is a naturally occurring amino acid. In the presence of polyphenol oxidase, tyrosine, abundantly found in the foot of mussels, is hydroxylated to dopa. This amino acid forms a very strong hydrogen bond with hydrophilic surfaces and a strong coordinate covalent bond with metals or semi-metals. Being oxidized to dopa-quinone, dopa residues function to crosslink protein molecules.
Dopa-based tissue adhesives are commercially available, identified as Cell-Tak™ (BD Bioscience Clontech) and MAP™ (Swedish BioScience Lab.). However, these products require as many as 10,000 mussels to make 1 gram of the foot protein. Such a low extraction yield and high production cost restrict the use of the adhesive. In practice, the products are used mainly in cell or tissue culturing.
In order to overcome the problems encountered in the prior art, Professor Cha, Postech University, Korea developed a method of extracting mussel foot proteins. A tissue adhesive developed on the basis of the method of Cha was found to have an adhesive strength four-fold higher than that of fibrin glues (Cha et al., Journal of Adhesion and Interfaces 2008). However, this method also, although much improved, does not provide a satisfactory production yield, which remains only at 50-60% in the course of protein purification.
Another tissue adhesive based on dopa was developed by Professor Phillip B. Messersmith in 2007. It was an injectable and bioadhesive polymeric hydrogel which is prepared from a PEG-diamine modified with glutamine substrates with the aid of an enzyme (Phillip B. Messersmith et al., U.S. Pat. No. 7,208,171 B2). The prepared hydrogel, however, retains a mechanical strength of approximately 100 Pa and has an adhesive strength that is as high as or twice as high as that of fibrin glue. Phillip B. Messersmith also developed an in situ gel-forming bioadhesive hydrogel based on branched-PEG or PMMA-PtBMA-PMMA triblock, both modified with dopa derivatives, and a surface coating method (Phillip B. Messersmith et al., US2008/0247984 A1, US2007/0208141 A1, US2008/04149566 A1, US2009/0163661 A1, US2003/0087338 A1, WO2008/049108 A1, WO2008/091386 A2).
The dopa derivative-conjugated hydrogel exhibits high adhesive strength, overcoming the previous problems. However, at least 30 sec is required for gelling and a toxic oxidant, such as NaIO4, FeCl3, etc., is used for hydrogel crosslinking.
There is therefore in the context of in situ formation, a great need for bioadhesive hydrogel that requires a short gelation time and exhibits excellent mechanical strength, good biocompatibility, proper biodegradation, and fast and strong adhesiveness even in the presence of water.